Fertility is the ability of a person to make children through mating with a person from the other sex. The ovaries in women and the testicles in men are vital organs to fertility in women and men, respectively. Ovaries and testicles (gonads) contain ‘gametes’ which are haploid cells (gametes contain half of the set of chromosomes found in the other human cells). The ovarian gametes are called ‘ova’, and the testicular gametes are called ‘sperm’. Healthy men are usually able to produce sperm from adolescence till late adulthood; conversely women are born with about 100,000 ova per ovary and with age this number decreases steadily; by puberty only about 30,000 ova per ovary survive, and from puberty till menopause only 300-400 ova ripens. Beside production of gametes, the gonads have vital functions related to hormonal production such as estrogen, progesterone and testosterone secretion which affects many organs in the body and changes in these hormones can result in a variety of problems such as libido disturbances, mood disorders, cardiovascular disease and bone density disturbances (osteoporosis). Moreover, suppression of the hormonal production in the gonads is utilized in treatment of cancer diseases: Castration (either surgical or chemical) is widely used to treat metastatic and locally advanced prostate cancer; and ovarian suppression is used to treat breast cancer patients suffering from tumors expressing estrogen or progesterone receptors. Gonadal function preservation and/or function modulation are needed in the following settings:    Fertility preservation in patients treated due to cancer disease.            a. Women. Cancer is the second cause of death in western countries. One out of ten women, on average, suffers from breast cancer. In 2008, approximately 182,000 women in the United States were expected to receive a diagnosis of invasive breast cancer, of these patients, an estimated 16,000 were younger than 45 years of age (1). ‘Chemotherapeutic agents routinely used for the treatment of breast cancer include cyclophosphamide, fluorouracil, doxorubicin, pa-clitaxel, and docetaxel. Alkylating agents, including cyclophosphamide, are quite toxic to the ovaries, particularly to the primordial follicles, which represent the ovarian reserve. Although the effect of chemotherapeutic regimes on fertility is predicated or the baseline ovarian reserve, treatment effects become particularly pronounced by the time patients reach 40 years of age.’ (1). As detailed in a recent review in the New England Journal of Medicine (1) ‘Several options are available to women with cancer who wish to preserve their germline. Patients may elect to delay cancer treatment in order to undergo one cycle of hormone stimulation, followed by cryopreservation of either a mature oocyte or an embryo. Both techniques require a delay in cancer treatment for up to 1 month; this may not be an option for some patients. Cryopreservation of mature oocytes is considered experimental, although more than 100 live births have been reported with the use of this technique,’ (1) ‘Fertility-preservation techniques that do not require hormonal exposure are available. Ovarian tissue can be obtained at the time of diagnosis without additional hormonal stimulation, thus only minimally interfering with the patient's treatment plan. Depending on the day of the menstrual cycle, oocytes may be aspirated from the ovary, matured in vitro, and then cryopreserved for later use. In addition, individual follicles or strips of ovarian cortical tissue can be cryopreserved directly for future use in either in vitro follicle maturation or tissue transplantation. Thus far, five live births have been reported in women with cancer who underwent autologous transplantation of cryopreserved ovarian tissue.’ (1)        b. Men. Men undergoing chemotherapeutic treatments and wish to preserve their fertility undergo usually sperm banking. When the patient and his spouse wish, the spouse undergoes insemination or in vitro fertilization. This method, although effective, do not preserves the natural fertility of the man, and these patients may suffer from chemotherapy induced oligospermia, which complicates the conception process. Moreover, if the banked sperm get lost or defective the patient's options for parenthood decrease.        e. Children. In the United States, 10,700 new cases of cancers were diagnosed in children in 2008 (1, 2). Of these patients, nearly 80% were expected to survive (2). Treatment regimens for childhood cancers are extremely toxic and pose a threat to the fertility of young patients (1). The current options for fertility preservation are limited in their effectiveness in both girls and boys (especially those before adolescence).            2. Women with hereditary genetic mutations in genes such as BRCA-1 and BRCA-2 are at increased risk for ovarian cancer. The current practice is to perform ovarian resection as early as possible to these women, preferably before the age of 25-30 years, before the development of cancer. Clearly, resection of the ovaries at young age results in compromise of the fertility in these women, as well as induces early menopause. Currently, there is no method to prevent or delay cancer development in ovaries of women with genetic mutations posing them at increased risk of ovarian malignancies.    3. Broadening the ‘fertility window’. As stated above, fertility of healthy women decreases with age. Above age 30-35 years it becomes more difficult for women to get pregnant. In the last century more and more women arrive to this age without children due to either career related issues or due to lack of appropriate spouse. These women seek methods to broaden the ‘time window’ of pregnancy beyond the age of 40 or 50 years. Currently, there is no solution for healthy women to broaden the fertility window.    4. Delaying menopause. By the age of 50 years most women arrive to menopause. Menopause results from lack of ovarian functionality, not solely lack of ovulation, but also lack of production of sex hormones (e.g. estrogen and progesterone). Beside its effect on fertility, the hormonal changes at menopause results in changes in almost every organ. Lack of estrogen results in faster aging, more heart diseases (atherosclerosis), and bone density changes (osteoporosis). Women beyond the age of menopause can use hormone replacement therapy to compensate for the hormonal changes that ovarian failure causes by menopause, and lower the development of osteoporosis, coronary heart disease, and changes to the skin texture.    5. Birth control. Family planning and pregnancy timing are widely used in the last decades by women. There are a variety of birth control methods available for women. This includes birth control pills, intrauterine device and a variety of mechanical barriers.    6. Polycystic Ovary Syndrome Polycystic ovary syndrome is one of the most common female endocrine disorders, affecting approximately 5%-10% of women of reproductive age (12-45 years old) and is thought to be one of the leading causes of female subfertility (6). Medical treatments of women with infertility due to polycystic ovary syndrome rely mainly on medications such as clomiphene citrate. Surgical treatment of infertility due to polycystic ovary syndrome include either ‘wedge resection’ of one ovary, or ‘ovarian drilling’ which can be done laparoscopically by making small holes in the ovarian coating or capsule with a laser or cautery needle. Ovarian wedge resection and ovarian drilling results in induction of ovulation in women suffering from polycystic ovary syndrome for a limited number of months after the procedure, providing the opportunity to these patients to get pregnant.    7. Treatment of breast cancer patients with ovarian suppression. Ovarian suppression, with the use of gonadotropin-releasing hormone analogues, plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer (8). Resection of the ovaries, is another alternative to ovarian suppression with long acting gonadotropin-releasing hormone analogues, but is usually reserved for women with hereditary breast and ovary genes mutations.
Use of Hypothermia to Protect Tissues and Organs from Chemotherapy.
Changes in temperature are used in limited situations in cancer patients to decrease exposure to chemotherapeutic drugs, and thus preserve the organ function:    1. Prevention of Chemotherapy-Induced Hair Loss with Scalp Hypothermia: Treatment of patients who suffer from cancer includes the administration of chemotherapeutic drugs such as doxorubicin and cyclophosaphamide which induce hair loss, alopecia, in many cases. Prevention of doxorubicin-induced hair loss with scalp hypothermia was reported in many controlled trails as early as the report in the New England Journal of Medicine in 1979 (4), Satterwhite et al. showed that scalp hypothermia resulted in preservation of hair in 75% of patients treated with doxorubicin as compared with 8% in the control group (5). The mechanism by which cooling results in preservation of hair is not well characterized, but is thought to be a combination of decreased exposure to chemotherapy during the cooling period, and decrease in the hair follicle metabolic rate, which culminates in resistance to chemotherapy. Because chemotherapy disturbs the normal metabolizing cell, cooling the cell, decreases its metabolism and puts a significant part of its functions ‘on-hold’ rending chemotherapy less active.    2. Hypothermia gloves are frozen gloves that the patient wears in order to protect fingers and nails from the side effects of chemotherapy (3). Onycholysis and skin toxicity occur in approximately 30% of patients treated with docetaxel. A multicenter study by Florian Scotté et al. (7) showed that frozen glove significantly reduces the nail and skin toxicity associated with docetaxel and provides a new tool in supportive care management to improve patient's quality of life. In this study, patients receiving docetaxel 75 mg/m2 alone or in combination with other chemotherapy were eligible for this case-control study. Each patient wore a frozen glove for a total of 90 minutes on the right hand. Onycholysis and skin toxicity were significantly lower in the frozen glove-protected hand compared with the control hand (P=0.0001). Onycholysis was grade (G) 0 in 89% v 49% and G1 to 2 in 11% v 51% for the frozen glove-protected hand and the control hand, respectively. Skin toxicity was G0 in 73% v 41% and G1 to 2 in 27% v 59% for the frozen glove-protected and the control hand, respectively (7).